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Messages - sifter

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I've had trouble with cyclical and ever increasing extreme fatigue, exhaustion and exercise intolerance for 10 years now. I've have Hashimoto's for 25 years, and RNP antibodies (MCTD) and was always an athlete. But treatment did not help the ever worsening prob and I'm now quite sedentary (not by choice) .

I first noticed that I could not bicycle 30 miles anymore, and chalked it up to "bad days" or getting older. But when distances reduced to 6 miles, then 3 miles followed by unreal exhaustion that can't be explained, and inability to get heart rate up above idle, it was pretty obvious something was very wrong. I'd go 4MPH and be flat out incapable of doing more. That's a universe away from 20 something racing speeds and 30+ mph sprints that were possible before this started. 

I am also very low T. Testosterone treatment makes no difference what so ever with regard to this. Makes me horny, but does nothing for the severe energy deficit.

I've just been accurately diagnosed with Multiple Mitochondrial Dysfunction (although it's been suspected for years) . It's not necessarily genetic, possibly caused by Statins. It's not good news, it's rare, but it's good to finally know. Knowing means I now understand that I must not push myself into fatigue, as I've been told damage occurs due to oxidative stress. Staying within my energy envelope is the directive.

One thing I learned on my own is that Prednisone helps, especially when I have extended troubles. Interestingly, certain Mito diseases may be responsive to glucocorticoids.

Quote from NCBI: Mitochondrial dysfunction can be precipitated by drugs, Hypothyroidism, renal and liver impairment and diabetes are other risk factors. Whilst evidence in the literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS, the exact processes leading to mitochondrial dysfunction are not yet fully understood.

I should never have been put on statins. Being both Athletic and Hypothyroid. It's ruined my life.

In any case, I'm wondering if anyone here knows anything about this kind of disease?

Hi cujet-
Have you had the occasion to take any Fluoroquinolone antibiotics in the past few years?
There is a side effect for this class of antibiotics which is known to damage mitochrondria.

It includes commonly prescribed Levaquin and Cipro.

You know it is bad when there is a BLACK BOX warning which the FDA required for these antibiotics.
It is bad enough so that there are class action lawsuits.
The mitochrondria damage can often result in a torn achilles and peripheral neuropathy. 
Unfortunately a lot of practitioners are not familiar.  (however the pharmacists are WELL aware...)

The FDA reinforced the warning recently since a lot of docs were giving it out like candy- basically "don't be giving these out for UTI's and such"- the side effects are real-
I am a senior athlete and had a lot of the symptoms you did-
google it-

Peak:  Yes, I agree.  Very refreshing to be with a doctor who is up on the latest research and is interested in preventive cardiology.

Boxcar:  Thanks for your reply. Yes, I had read the same info about RYR supplements.  However, my doctor seems to feel that the brand he is giving me has enough of the active ingredient.  Its not supposed to be available for general sale, or is at least labeled that way: "For professional use only".  Maybe that is how they are getting around the FDA.  Not sure, but it seems to be working.  I am taking 3 x 1000 mg of purified fish oil (supposedly mercury free).  No issues with stomach upset or bleeding. I don't take NSAIDs or aspirin.  I had an issue with Advil a few years ago, it lead to some stomach problems.  As an avid exerciser, we tend to pop "vitamin I" too much (Ibuprofen). 

I take methylated B vitamins because I am MTHFR positive, and have (had) high homocysteine.  I think having the right type and amount of these vitamins have helped restore my energy levels (along with TRT of course).  One of the B vitamin complexes I take has a pretty beefy dose of Niacin in it, so my doctor feels like that is enough given my lipid profile.

On your other question, my doctor ordered all of these tests through Boston Heart Diagnostics (www.mybostonheart.com).  He has a deal with them, so it didn't cost me much out of pocket ($80), but the EOB from my insurance company showed over $3,000!  I think you can get an advanced lipid panel through Discounted Labs for a reasonable price that will pull a lot of the same markers.

I'll add my own experience with Red Yeast Rice-
I am a fan of Consumerlabs, which commonly tests Red Yeast Rice among other supplements.  They publish information on the amount of monacolin-k in each, also known as Lovastatin...
It is hard to get true information on this active ingredient since the FDA says manufacturers telling folks this information makes it a drug (my view is that there are too many people trying to protect RX statin profits...)
Consumerlabs also screens for impurities.

What Consumerlabs found is that since supplement manufacturers are not allowed to disclose this information, there is a wide range of dosages in the available products.  They tested a number of RYR supplements. 

Based their analysis of the available scientific information, you need at least 10mg of monacolin-k in order to get the lowest effective dose- and I am all about lowest effective dose.

One of their suggestions was to use the brand HPF Cholestine.  You can use their product at half dosage and still get about 12 mg of monacolin-k.  I started taking a half dose about 4 months ago. My cholesterol went down 24%.  A very inexpensive approach.  I had no side effects...
I suppose a full dose would yield even better results-


Why not just pay for it? It's $130 and lasts for months.  I get 10ml bottles from Walgreens and I pay $110 which last 5 months. 
Contamination is not gonna happen either.

My doctor writes my prescription with 4 - 1 ml vials per refill.   So with insurance, I am paying 22 dollars for what you are paying 110 dollars for.

So you're just saying to be sure to talk to your doc, because there may be a much cheaper insurance-friendly option ?

I am saying that if your insurance covers it, and your doc writes your prescriptions to where you get one vial per injection (they are assuming you draw half of it and then throw the rest away per vial), then you are getting 4 - 1ml vials per refill of test cyp, which is 800 mg of test cyp for a 10 dollar prescription copay.

If your insurance is not generous....  I would second the comments earlier about using GoodRX.  My scripts were changed to the 1ml vials- I get three for about $23 at CVS.
I can understand for some it is a little difficult to get the dosage to come out right without a lot of waste with the 1ml vials- I avoid this by using a disposable 17ga needle to draw the entire contents of a 1ml vial, then back-load my correct dose into a 30ga pin.  I can load up a month's worth of 30ga pins at a time.  (and it keeps my 30ga pins sharp...)  I inject subq eod.

Okay, you guys know I've been a fan of DIM, and have been using it, for years, but could never quite explain how it works, only pointing out what the following site explains:

  • There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathway leads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIM works to improve our health.

Okay, so we have 2-, 4-, and 16- hydroxyestrogens, all of which are metabolites of estradiol.  Turns out these three metabolites are also broken down further (e.g., 2-hydroxyestrogen is made up of 2-hydroxyestrone, which becomes 2-methoxyestrone). 

Now consider this comprehensive graph which catalogues most (but not all) of the estrogen metabolites, and remember to scroll right because I couldn't find a way to make the graphic smaller:

So you have estrone and estradiol (17b-estradiol) which go back and forth, and from both (probably more from estradiol) you have three arrows: the left that breaks down to 2-hydroxyestrone, the middle 4-hydroxyestrone, and the right 16a-hydroxyestrone.  Remember what the excerpt from the link I posted above said: 2-hydroxyestrogens (which includes the -estrone and -estradiol) are good, and 4- and 16(a)-hydroxyestrones are bad.

Next step.  Not included in this graphic is that each arrow stands for an enzyme (which is responsible for the metabolism of one chemical to another), and more specifically a gene that codes for an enzyme: the first arrow stands for a gene/enzyme CYP1A1, the second arrow CYP1B1, and the third arrow I dunno what but it ain't relevant to our discussion.  It's very important to grasp this basic idea, because the rest of this post uses these arrows/enzymes as premises from which other conclusions follow.  When I mention CYP1A1 being upregulated or increased, this means the first arrow "leaks away" estradiol toward what it points to, 2-hydroxyestrone (which in turn means the rest of the chain below this metabolite is increased).  Same thing with CYP1B1.  Also important here: because CYP1A1 leads to increasing the pathway that shunts estradiol to 2-hydroxyestrone, and 2-hydroxyestrone is a good, non-carcinogenic estrogen, we want CYP1A1 to be increased; and because CYP1B1 leads to the increase of a bad, carcinogenic estrogen, 4-hydroxyestrone, we want CYP1B1 to be decreased.  Also note that any time either of these enzymes, CYP1A1 or 1B1, are increased, this by definition means that 16a-hydroxyestrone is decreased, because the upregulations of CYP1A1/1B1 shunt estrogen away from 16a-hydroxyestrone, which is also considered to be carcinogenic, so we want this to happen.  Got it? 

Okay, so how does DIM help? 

This abstract notes how DIM increases all three relevant CYPs:

  • Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1 beta-(3)H-androstenedione to estrone and (3)H(2)O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0--30 nM) and DIM (0--10 microM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC(50) values of about 0.3 nM and 3 microM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 microM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 microM) significantly increased mRNA levels for all three CYPS: DIM analogs with substitutions on the 5 and 5' position (3 microM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPS: In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.

Whoa, whoa, whoa, wait.  DIM increases the activity of the aromatase enzyme CYP19 up to 2-fold?  What.  The.  Heck.  This means that DIM is, in a very real sense, an anti-aromatase inhibitor.  But why the heck do guys tend to feel positive benefits from it?  That would have to do, presumably, with the next point: DIM also increases the activity of CYP1A1 and CYP1B1.  But wait!  CYP1B1 (look at the graph above) leads to the conversion of estrone/estradiol to 4-hydroxyestrone, which is a bad, cancer-producing estrogen pathway.

So it's not looking great for DIM so far: not only does it (so strangely) seem to increase aromatase (CYP19), but it also increases the proliferation of 4-hydroxyestrogens!  But guys feel better on it.  Therefore, the effect of DIM on CYP1A1 must explain why guys feel better and counterbalances the negative effects of DIM on aromatase and 4-hydroxyestrogens.  Well then! 

Dr Crisler (under his old pseudonym, SWALE, on a pretty old Meso-Rx forum post) writes the following:

  • I have seen two such studies which showed that DIM stimulated not only the CYP1A1 enzyme, thus increasing 2-OHE, but also the CYP1B1, which is why 4-OHE concentrations rise as well. TMG, or its child, DMG, provides methyl groups, thus helping wash the 4-OHE downstream. IF (and it's a big IF) this is true, in vivo, DIM should not be taken without a methyl donor, and would be especially dangerous in someone with a COMT enzyme deficiency.

So Dr Crisler recommends taking a methyl donor (TMG/betaine is just one option, the others being methylB12, methylfolate, etc.) in order to drain the increase 4-hydroxyestrogens as a result of DIM increasing the CYP1B1 enzyme pathway.  Therefore, any guy who takes DIM, assuming Dr Crisler's reasoning is correct (and he's cautious enough to admit that it might not be), should take a methyl donor.  But hey, it's good news for the vast majority of people to take methyl donors, so it wouldn't hurt.  Moral of the story: take a methyl donor with DIM just to be safe, and if you don't see any positive benefits from taking DIM, maybe adding a methyl donor could help in this regard.   

But let's go back to something I've said many times in other places: it seems like a lot of guys who take DIM and get a positive response from it can't really pick up on any noticeable changes in estradiol measured by a lab as a result of taking it.  Follow me here: if DIM results in increases in CYP1A1 and CYP1B1, this means that estradiol is "leaked away" to these other pathways which are upregulated, leading to increases in 2- and 4-hydroxyestrogens.  But if DIM also increases aromatase activity, perhaps this effect is canceled out (such that increases in aromatase and therefore estradiol are negated by decreases in estradiol from the increase in its conversion to 2- and 4-hydroxyestrones), and this is why we usually don't see decreases in estradiol for guys who take DIM.  This also theoretically means that some guys could see decreases in estradiol given their unique biochemistry, and also the reverse by seeing increases in estradiol if the increase in the aromatase enzyme overpowers the increase in the CYP1A1 and CYP1B1 enzymes mentioned above. 

So it seems like DIM could be a bit of a wild card, and this could explain its success or lack thereof for different guys: for some guys it increases estradiol (too much aromatase increase and not enough upregulation of CYP1A1 and CYP1B1 to cancel out this effect), others does nothing noticeable to estradiol (aromatase and CYP1A1/1B1 cancel each other out), and others see reductions in estradiol (any increases in aromatase activity are offset by upregulation of CYP1A1/1B1, which "leak away" more estradiol than the increase in aromatase produces). 

Okay, case closed, right?  Not quite.  We have another supplement to consider, indole-3-carbinol, from which DIM is a metabolite.  The study titled "Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent." points out the following juicy bit:

  • We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1.

Whoa!  So somehow Indole-3-carbinol, unlike DIM, sharply decreases CYP1B1, resulting in lower levels of the carcinogenic 4-hydroxyestrogens.  Unfortunately, no mention of aromatase (CYP19) was made in the abstract of the article.  What this all means is that I-3-C could be advantageous over DIM because it only increases CYP1A1 and decreases CYP1B1, whereas DIM increases both of these enzymes.  But, as said above, if you take DIM with a methyl donor, you're going to take care of the increase in 4-hydroxyestrogens from the increase in CYP1B1 DIM offers.  Therefore, DIM + methyl donor = I-3-C, and because we don't know of the effects of I-3-C on aromatase, we can't make any conclusions. 

So is DIM or Indole-3-carbinol better?  That depends on how you take them.  If you take DIM by itself, it will increase both 2- and 4-hydroxyestrone pathways, the first being a "good" estrogen pathway and the second being a "bad", carcinogenic pathway.  But, per Dr Crisler's statement, if you take a methyl donor (e.g., betaine, methylB12, etc.) you "drain away" any increases in the 4-hydroxyestrone pathway (presumably through increasing the COMT enzyme which converts hydroxyestrogens to methoxyestrogens).  DIM also increases aromatase, but we don't know if I-3-C does as well, but seeing how DIM is a metabolite of I-3-C, it's safe to assume that I-3-C probably does increase the aromatase (CYP19) enzyme as well.  I-3-C, on the other hand, appears to increase the CYP1A1 pathway (leading to an increase in the "good" estrogens) while sharply reducing the CYP1B1 pathway (leading to an increase in the "bad" carcinogenic estrogens).  So basically it seems like taking I-3-C could be less work than taking DIM, which you would have to take with a methyl donor to negate the damage done by increasing the 4-hydroxyestrone pathway.  But heck, since we should all be taking methyl donors, there's really no damage done by just taking DIM.

Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

Nice post Kierkegaard-

It gets at the center of a problem I have been wrestling with-
Managing both the 2-hydroxy and 4-hydroxy estrogen metabolites so that cancer risk is diminished-

For a long time I could not crack the methylation of both of these (my 24-hr hormone urine tests consistently poor)
I solved the conversion of the 2-hydroxy estrogens using DIM, and my 2-hydroxy and 2/16 labs looked great for the first time. 

At the same time I was managing my overall methylation (as I have a methylation SNP which is impaired).  My methylation is doing well now, in part because I am taking 4000mg of TMG/day (some consider 3000mg to me a minimum effective amount).

So I am one of those folks taking TMG with my DIM.  However, I have not been able to see likewise improvements with the 4-hydroxy estrogens, and it confounded me a bit.  Clinical evidence re supplementing to manage this estrogen seems to be scarce.

For this reason I was interested in your note about IC3 being a possible solution for managing 4-hydroxy.  There are DIM products out there which are combination DIM/IC3 formulations, but I have stayed away from them because the recent science seems to imply DIM being a safer choice-


Having said that, the Bioresponse folks  (in the link and who make a very good DIM) are somewhat invested in their analysis.

Still looking for a balanced view...


Yea minimizing gluten is basically what I am doing as it only presents obvious issues after a given threshold.

That basically means stuff like sandwiches, pita bread,regular pasta, noodles, etc is out of question but breaded stuff with just a little bit is still ok.

Hi Electrify
I think after you got into it you would find that a GF diet is not as difficult.  I am a celiac and have been on a GF diet for 8 years.  I had a sharp wellness doctor that spotted it and I was quite a skeptic at first, but the evidence became irrefutable.
You can eat pretty well going gluten free. Think of it- all meats, all seafood, all vegetables, pretty much all fruits are available to you. IMHO, one could argue that the limitations of fast food options, while inconvenient, may not be in the best interest of your long term health anyway...whether you are sensitive or not...

And with some experience, you can even navigate the fast food places...

My .02 cents....

Crisler has me on 150 iu per day.  If I miss days here and there, no big deal.

Are you on TRT?
Yup, current protocol is 50 mg twice a week sq and 150 iu of hcg daily.  Just transitioned to this new protocol about a month ago.  I need to get new bloodwork done as I think I need to bump my t cyp up a bit based on how I am feeling.

Hi Bear:

I recall Dr. Crisler's previous protocol for TRT patients supplementing with HCG was adding up to 500I.U. per week on top of the TRT regimen.

It sounds like he has modified/relaxed this threshold- are you aware if he is proposing a new weekly maximum with other patients as well?

Anyone aware if he has articulated a new weekly upper limit?


I have seen a lot of benefit from HRT- but I have noticed a ton of doctors who will throw T at a patient without much knowledge or experience of steroidogenic pathways or without testing their patient on his related metabolites.

It is easy for me to believe that HRT-done-poorly, has the potential for negative consequenses as bad as hormone imbalances that exist prior to HRT.

My HRT doc, who was originally an Internal Medicine MD, recently told me that there was a new Board Certification being established for Functional Medicine.  I'm curious to see if this will ultimately result in a more formalized, best-practices protocol for HRT.

There are many guys who use HCG alongside their TRT and receive fantastic benefits; and there are others who do TRT solo. My question is how would TRT with DHEA/pregnenolone compare to doing TRT with HCG? I want to backfill the pathways that have been suppressed from TRT; however my doc isn't definite about adding HCG alongside my TRT, just yet.

Definitely worth a shot!  As you probably know, exogenous testosterone shuts down the P450scc enzyme which converts cholesterol to pregnenolone.  Consequently, very insightful docs are down with supplementing pregnenolone to (as you say) backfill the lowered preg from exogenous T.  Some guys even supplement with both preg and progesterone, presumably because you can only do so much with supplementation and therefore a limited (but significant) amount of preg will convert to DHEA and progesterone (which will eventually convert to cortisol).  To me, the most important benefit with going HCG plus T is keeping your cortisol up to snuff; however, there are also inherent advantages to preg, progesterone, and DHEA, such as preg's ability to help cognition.

What's the difference between backfilling and HCG?  The latter keeps the P450scc enzyme afloat, yielding a more organic functioning of the pregnenolone line rather than the artificial supplementation.  HCG keeps the enzyme afloat through LH, which also means you'll get a double whammy of normally functioning preg as well as fertility.  If that's important to you.

Some guys even take HCG while supplementing with preg, because as we age our leydig cells die, so HCG loses its effect, causing less of the activation of the P450scc enzyme. 

If you supplement, go with sublingual or transdermal preg or progesterone, because with oral supplements your liver kills a lot of the bioavailability.

Very good info Kierkegaard! Thank you!  So, because of the HPTA suppression from exogenous T, would this limit supplemental DHEA/pregnenolone from converting to their metabolites like 4-dione, progesterone, and cortisol via lack of their enzymes or in the abscence of LH?

That's the theory!  And one that Crisler et al. ascribe to.  But like with Peak, it's hard to find solid evidence for it.

Ok, I'm confused. Are you saying that supplemental DHEA and pregnenolone without HCG  have the ability to convert to their metabolites; or are you saying that without HCG  the supplements can't convert to their metabolites?

Theoretically the former.  As I see it, HCG (because it restores P450scc through LH function) is the "real deal" whereas preg/prog/DHEA supplementation is the fake one, both of which would restore the pregnenolone line (but presumably HCG would be better at it since it's more "organic").

I agree with Kierkegaard and some of the other posters- Both my Prog and Preg were crushed low out of range as I normalized my Test levels with HRT.  I was using a low-dose Progesterone in an attempt to backfill.  Have also considered some transdermal Preg but my doc had some concerns about where it would convert to- It is high up on the master hormone path-How do you direct it?

For this reason I just started limited dose HCG with my Test Cyp HRT.  Trying to see if the ancillary production of Preg and Prog by the testes will backfill so that my levels will improve to like it was before I started my Test Cyp.  I use The Genova Complete Hormones (Urine) to evaluate my levels.  BTW Genova publishes an interesting "Steriodogenic Pathways" chart :

If it does not help to backfill these, I'll re-visit individual supps instead.


FDA announcement - recent

LEF folks on board from 2008 when testing was just starting

Now mainstream enough for Dr Oz to pitch it- video  (but I'm not an OZ fanboy)

Noticed that Quest is offering as a standard assay-

Wondering if is a new inexpensive tool to evaluate the state of our arteries-

Hi Peak-

Have not seen it mentioned in the forum but was interested to see if you have looked at the new PLAC Test -

It is getting a ton of media play and apparently is an inexpensive blood serum test-


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